Abstract 14515: Raising HDL With CETP Inhibitor Torcetrapib Improves Insulin Resistance and Modulates in vivo Tissue Glucose Uptake in Dyslipidemic and Insulin Resistant Hamsters
Objectives: Recent studies suggest that high density lipoprotein (HDL) particles have the potential to stimulate glucose uptake in skeletal muscle and inhibit adipocyte lipolysis. Here we investigated whether raising HDL-cholesterol levels with cholesteryl ester transfer protein (CETP) inhibition improves insulin resistance in dyslipidemic and insulin resistant hamsters.
Methods and results: Hamsters were made dyslipidemic and insulin resistant with a 2-week high fat/fructose enriched diet and were then treated daily with vehicle or CETP inhibitor torcetrapib 30mg/kg (TOR) for 10 days.
Compared to vehicle, TOR significantly increased HDL-cholesterol levels by 38%, with higher apolipoprotein A-I and apolipoprotein E levels in HDL particles. As expected, TOR altered macrophage-to-feces reverse cholesterol transport, with significantly higher 3H-tracer appearance in HDL, but not in feces, over 72 hours after 3H-cholesterol labeled macrophages i.p. injection.
TOR reduced fasting plasma triglycerides, glycerol and free fatty acids levels by 65%, 31% and 23%, respectively (all p<0.01 vs. vehicle). TOR also reduced blood glucose levels and plasma insulin by 20% and 49% respectively (both p<0.01 vs. vehicle), which led to a 60% reduction in HOMA-IR index (p<0.01).
To evaluate the effect of TOR on individual tissue glucose uptake under insulin-stimulated state, hamsters were injected i.v. with 3H-2-deoxyglucose and insulin (0.4mU/kg). Surprisingly, glucose uptake was significantly reduced by 24 and 27% in visceral and subcutaneous adipose tissue in hamsters treated with TOR. While TOR did not affect glucose uptake in the glycolytic extensor digitorum longus muscle, a 26% increase was observed in the oxidative soleus muscle (p<0.01 vs. vehicle). TOR also increased glucose uptake significantly in liver and heart by 33 and 70%, respectively.
Conclusion: Raising HDL levels with the CETP inhibitor torcetrapib improves insulin resistance and modulates in vivo glucose uptake in dyslipidemic and insulin resistant hamsters. Whether similar effect would be observed with other CETP inhibitors remains to be investigated.
- © 2013 by American Heart Association, Inc.